Stereoselective synthesis of pentacyclic steroids functionalized at C-11

Article abstract of DOI:10.1016/j.steroids.2012.04.004

We set out to describe an efficient and versatile method for preparing pentacyclic steroids diversely substituted at C-11 from cholic acid, via a stereoselective epoxidation and the epoxide opening as the key steps. The characteristic ¹H and ¹³C NMR spectroscopic features of the synthesized compounds are reported.

Full text of DOI:10.1016/j.steroids.2012.04.004

Steroids 77 (2012) 1092–1100
Contents lists available at SciVerse ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Stereoselective synthesis of pentacyclic steroids functionalized at C-11
⇑
Malika Ibrahim-Ouali , Eugénie Romero, Khalil Hamze
Institut des Sciences Moléculaires de Marseille UMR 7313 CNRS and Université d’Aix Marseille, Faculté des Sciences et Techniques de Saint Jérôme,
Avenue Escadrille Normandie Niémen, 13397 Marseille, Cedex 20, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 March 2012
Received in revised form 30 March 2012
Accepted 4 April 2012
Available online 26 April 2012
We set out to describe an efficient and versatile method for preparing pentacyclic steroids diversely
substituted at C-11 from cholic acid, via a stereoselective epoxidation and the epoxide opening as the
key steps. The characteristic 1H and 13C NMR spectroscopic features of the synthesized compounds are
reported.
Ó 2012 Published by Elsevier Inc.
Keywords:
Pentacyclic steroids
Epoxide
Lactones
Amines
Thiols
1. Introduction
pentacyclic steroids derived by the fusion of a carbocyclic ring to
a heterosteroid skeleton are known to exhibit interesting and
Steroids represent an important class of natural products due to
their high ability to penetrate cells and bind to nuclear and mem-
brane receptors. The steroid system, selected by the evolutionary
process to perform some of the most fundamental biological func-
tions, has not only inspired biochemists and endocrinologists, but
has also become the basis of many important discoveries in organic
chemistry.
The fact that minor changes in steroid structures can cause
extensive changes in biological activity has long intrigued medici-
nal chemists. Naturally occurring steroid nuclei have been modified
in several ways with the aim of finding more active compounds,
free from undesirable or harmful side effects, and of recognizing
the structural and stereochemical features required for the display
of specific, selective physiological activity.
Bile acids (BA) have been the subject of numerous pharmaco-
logical studies. Their amphiphilic character generally increases cell
membrane permeability. As they enhance the absorption of hydro-
phobic drugs, they can be used to improve the delivery of drugs
that specifically target the liver [1]. Some bile acid derivatives
are potent antibiotics against Gram-negative bacteria [2,3].
Otherwise, pentacyclic steroids constitute an important class of
steroids. There are many examples of pentacyclic steroidal deriva-
tives of pharmacological and biological importance [4,5]. Pentacy-
clic steroids obtained by fusion of a carbocyclic ring such as
benzene or cyclohexane or cyclopentane to the steroid nucleus or
diverse biological properties [6–9].
So, it would be interesting to introduce a new ring and a new
function at the C-11 position of the steroidal skeleton which is a
key position from a biological point of view [10–14], in order to ob-
tain a new class of steroids. We report herein an efficient stereose-
lective synthesis of pentacyclic steroids from cholic acid (Scheme
1). We show that we can introduce by our method not only an amine
but also a thiol function or a selenium at the C-11 position of the
steroidal skeleton. We report here the full details of these syntheses.
2. Experimental section
All reactions were run under argon in oven-dried glassware. 1
H
and 13C NMR spectra are recorded at 200 or 400 and 50 and
100 MHz respectively, in CDCl3 solutions. Chemical shift (d) are
reported in ppm with tetramethylsilane as internal standard. IR
spectra were recorded on a Perkin-Elmer 1600 spectrophotometer.
Flash chromatography was performed on silica gel (Merk 60 F254
and TLC on silica gel. Dichloromethane was distilled from P2O5
and tetrahydrofuran (THF) over sodium/benzophenone.
Compounds 4 and 5 were prepared according to the previously
described procedure [15]. The nomenclature used for the steroids
is not the nomenclature used by chemical abstracts [16,17].
)
2.1. Methyl 3a,7a-diacetylcholan-11-enate (5)
⇑
A
mixture of anhydrous hexamethylphosphoric triamide
Corresponding author. Tel.: +33 491288416; fax: +33 491983865.
E-mail address: malika.ibrahim@univ-cezanne.fr (M. Ibrahim-Ouali).
(100 mL), potassium acetate (40 g, 0.4 mmol) and methyl 3,7-
0039-128X/$ - see front matter Ó 2012 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.steroids.2012.04.004

M. Ibrahim-Ouali et al. / Steroids 77 (2012) 1092–1100
1093
O
O
11
O
HO
OH
R
H
AcO
OAc
HO
OH
H
1
R = NHR', SR', SO2R', SeCN
Scheme 1. Retrosynthetic pathway.
diacetyl-12-mesylcholate 4 (10 g, 17 mmol) was heated at 100 °C
under argon for 48 h. The reaction mixture, which became slightly
yellow and viscous, was poured into water and ice (1 L). The white
solid product that precipited was allowed to coagulate and solidify
in the refrigerator for at least 3 h before filtration. The solid collected
was washed thoroughly with water to give the crude product. This
latter was recrystallized slowly from methanol and water to give
pure methyl 3,7-diacetylchol-11-enate 5 (6.7 g, 80% yield) as color-
less needles. mp = 139–141 °C; 1H NMR (CDCl3) 6.15 (dd, J = 2.8,
10.1 Hz, 1H, H-11), 5.45 (dd, J = 1.7, 11.8 Hz, 1H, H-12), 4.96 (m,
1H, H-3b), 4.59 (m, 1H, H-7b), 3.65 (s, 3H, OCH3), 3.16 (d,
J = 4.02 Hz, 1H, H-11), 2.72 (m, 1H, H-23), 2.05 (s, 3H, CH3C@O),
2.01 (s, 3H, CH3C@O), 1.00 (d, J = 6.2 Hz, 3H, H-21), 0.88 (s, 3H, H-
19), 0.72 (s, 3H, H-18); 13C NMR (CDCl3) 174.6, 170.6, 170.4, 139.1,
135.2, 73.9, 71.3, 62.6, 51.5, 49.2, 45.0, 40.2, 36.6, 36.3, 35.9, 35.2,
32.6, 31.8, 30.9, 30.8, 28.4, 26.7, 23.0, 22.4, 21.6, 21.6, 21.5, 18.3, 16.7.
2.4. Methyl 3
cholan-24-one (7a)
a
,7
a
-diacetyl-11b-phenylamino-12
a
-oxo-5b,17b-
Yield 235 mg (81%). Oil. IR (neat) 3509, 3236, 1736, 1606,
1511 cm–1 1H NMR (300 MHz, CDCl3): d = 7.30 (m, 5H), 5.29 (s,
;
2H, NCH2Ph), 4.85 (m, 1H, H-3b), 4.42 (d, J = 4.1 Hz, 1H, H-12),
3.51 (m, 1H, H-7b), 3.06 (dd, J = 3.6, 3.9 Hz, 1H, H-11), 2.03 (s,
3H, CH3C@O), 2.02 (s, 3H, CH3C@O), 1.04 (d, J = 5.4 Hz, 3H, H-21),
0.98 (s, 3H, H-19), 0.77 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3):
d = 173.2, 170.6, 170.5, 138.5, 128.7 (2C), 127.8 (2C), 127.5, 92.1,
71.8, 71.0, 53.4, 53.5, 50.1, 43.8, 43.7, 43.6, 42.2, 40.7, 39.4, 35.1,
35.0, 34.9, 34.8, 34.4, 33.3, 31.7, 31.5, 30.8, 23.6, 21.6, 21.5, 18.4,
11.9. HRMS Calcd. for C35H49NO6 579.356, found 579.3564.
2.5. Methyl 3
5b,17b-cholan-24-one (7b)
a,7a-diacetyl-11b-(p-methoxyphenyl)amino-12a-oxo-
Yield 200 mg (65%). Oil. IR (neat) 3447, 2940, 1732, 1608 cm–1
;
2.2. Methyl 3
Methyl 3
a
,7
a
-diacetyl-11
a,12a-epoxy-5b-cholan-24-oate (6)
1H NMR (300 MHz, CDCl3): d = 6.98 (d, J = 8.5 Hz, 2H), 6.62 (d,
J = 8.5 Hz, 2H), 5.28 (s, 2H, NCH2Ph), 4.82 (m, 1H, H-3b), 4.36 (d,
J = 4.0 Hz, 1H, H-12), 3.76 (s, 3H, OCH3), 3.49 (m, 1H, H-7b), 3.12
(dd, J = 3.4, 3.8 Hz, 1H, H-11), 2.01 (s, 3H, CH3C@O), 1.98 (s, 3H,
CH3C@O), 1.02 (d, J = 5.7 Hz, 3H, H-21), 0.97 (s, 3H, H-19), 0.75
(s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 173.3, 170.6, 170.5,
160.5, 129.9 (2C), 128.8, 115.6 (2C), 91.8, 71.3, 70.9, 56.2, 53.1,
52.9, 50.4, 43.9, 43.6, 42.9, 42.2, 40.6, 39.6, 35.7, 35.2, 34.6, 34.2,
33.8, 32.9, 31.6, 31.1, 29.8, 23.7, 21.2, 20.8, 17.9, 11.7. HRMS Calcd.
for C36H51NO7 609.3666, found 609.3671.
a,7
a
-diacetylchol-11-enate 5 (1 g, 2 mmol) was dis-
solved in CH2Cl2 (15 mL), under argon. The solution was cooled
at 0 °C and MCPBA (380 mg, 2.2 mmol) was added. After stirring
at room temperature for 24 h, the mixture was hydrolyzed with
a saturated solution of NaHCO3 (20 mL). The aqueous layer was
extracted with CH2Cl2 (3 Â 25 mL). The organic phase was dried
with MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (petroleum ether/
ethyl acetate: 4/6), to afford 930 mg (92% yield) of epoxide 6.
mp = 166 °C; IR (neat) 1305, 1220, 790 cm–1 1H NMR (CDCl3)
;
4.85 (m, 1H, H-3b), 4.58 (m, 1H, H-7b), 3.65 (s, 3H, OCH3), 3.16
(d, J = 4.02 Hz, 1H, H-11), 2.99 (d, J = 4.15 Hz, 1H, H-12), 2.04 (s,
3H, CH3C@O), 2.02 (s, 3H, CH3C@O), 1.03 (d, J = 6.0 Hz, 3H, H-21),
0.99 (s, 3H, H-19), 0.78 (s, 3H, H-18); 13C NMR (CDCl3) 174.6,
170.8, 170.4, 76.3, 73.6, 70.7, 60.6, 53.3, 51.5, 50.2, 43.7, 42.1,
40.5, 35.0, 34.9, 34.8, 34.7, 34.3, 31.6, 30.9, 30.6, 27.2, 26.8, 23.5,
21.7, 21.6, 21.4, 18.3, 11.9. HRMS Calcd for C29H44O7 504.3087,
found 504.3092.
2.6. Methyl 3
cholan-24-one (7c)
a,7a-diacetyl-11b-phenylamino-12a-oxo-5b,17b-
Yield 250 mg (88%). Oil. IR (neat) 3410, 2960, 1728, 1362,
1064 cm–1 1H NMR (300 MHz, CDCl3): d = 7.45 (m, 5H), 4.48 (d,
;
J = 3.9 Hz, 1H, H-12), 4.32 (m, 1H, H-3b), 3.62 (m, 1H, H-7b), 3.18
(dd, J = 3.1, 4.0 Hz, 1H, H-11), 2.04 (s, 3H, CH3C@O), 2.02 (s, 3H,
CH3C@O), 1.06 (d, J = 6.1 Hz, 3H, H-21), 0.96 (s, 3H, H-19), 0.76
(s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 174.1, 170.3, 170.2,
148.5, 129.7 (2C), 118.2, 114.6 (2C), 91.4, 72.0, 71.7, 50.1, 48.9,
44.7, 44.6, 43.2, 39.2, 35.4, 35.1, 34.6, 34.0, 33.8, 31.7, 31.2, 30.6,
28.4, 27.6, 27.1, 23.8, 21.7, 21.3, 18.3, 11.8. HRMS Calcd. for
2.3. General procedure for the epoxide ring opening
To a solution of epoxide 6 (0.5 mmol) in anhydrous EtOH/tolu-
ene (1/1) (15 mL) an amine or a thiol (2.5 mmol) was added drop-
wise over a period of 5 min under an argon atmosphere. The
solution was heated at reflux for 24 h. The solvent was then evapo-
rated and the product dissolved in dichloromethane (20 mL). The
mixture was hydrolyzed with a saturated solution of NaHCO3
(10 mL). The aqueous layer was extracted with CH2Cl2
(3 Â 25 mL). The organic phase was dried with MgSO4, filtered
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (typically eluting with CH2Cl2: MeOH,
95:5 for 7 or petroleum ether: diethyl ether, 9:1 to 7:3 for 8) to give
the corresponding 11-amino lactone 7 or 11-thio lactone 8.
C34H47NO6 565.3403, found 565.3408.
2.7. Methyl 3
5b,17b-cholan-24-one (7d)
a,7a-diacetyl-11b-(4-methylphenyl)amino-12a-oxo-
Yield 195 mg (67%). Oil. IR (neat) 3386, 1713, 820 cm–1; 1H NMR
(300 MHz, CDCl3): d = 7.01 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.3 Hz,
2H), 4.52 (d, J = 3.8 Hz, 1H, H-12), 4.48 (m, 1H, H-3b), 3.54 (m,
1H, H-7b), 3.12 (dd, J = 3.6, 4.1 Hz, 1H, H-11), 2.38 (s, 3H, CH3Ph),
2.03 (s, 3H, CH3C@O), 2.01 (s, 3H, CH3C@O), 1.01 (d, J = 6.1 Hz,
3H, H-21), 0.97 (s, 3H, H-19), 0.82 (s, 3H, H-18); 13C NMR

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M. Ibrahim-Ouali et al. / Steroids 77 (2012) 1092–1100
(75 MHz, CDCl3): d = 173.6, 170.6, 170.4, 138.9, 133.1, 127.6 (2C),
127.1 (2C), 90.6, 73.6, 72.7, 47.9, 47.2, 45.2, 44.7, 39.6, 38.2, 35.7,
35.3, 34.2, 34.2, 33.8, 31.6, 31.7, 31.2, 28.4, 27.6, 27.2, 24.3, 24.0,
21.4, 21.1, 17.9, 11.4. HRMS Calcd. for C35H49NO6 579,356 found
579.3564.
2.12. Methyl 3
24-one (7i)
a,7a-diacetyl-11b-butylamino-12a-oxo-5b,17b-cholan-
Yield 205 mg (75%). Oil. IR (neat) 3434, 1716, 1264, 1125 cm–1
;
1H NMR (300 MHz, CDCl3): d = 4.42 (d, J = 3.7 Hz, 1H, H-12), 4.19
(m, 1H, H-3b), 3.43 (m, 1H, H-7b), 3.16 (dd, J = 3.6, 3.9 Hz, 1H,
H-11), 2.66 (m, 2H, CH2NH), 2.02 (s, 3H, CH3C@O), 2.01 (s, 3H,
CH3C@O), 1.16 (d, J = 6.3 Hz, 3H, H-21), 1.06 (t, J = 6.4 Hz, 3H,
CH3) 0.92 (s, 3H, H-19), 0.77 (s, 3H, H-18); 13C NMR (75 MHz,
CDCl3): d = 174.1, 170.9, 170.3, 90.2, 74.6, 73.1, 51.2, 50.1, 47.6,
45.9, 45.1, 43.6, 38.7, 35.4, 34.9, 34.6, 33.6, 32.9, 31.4, 31.1, 30.7,
28.6, 27.5, 27.2, 24.1, 23.4, 21.4, 21.1, 20.6, 18.4, 15.7, 11.6. HRMS
Calcd. for C32H51NO6 545.3716, found 545.3719.
2.8. Methyl 3
a,7a-diacetyl-11b-(4-methoxyphenyl)amino-12a-oxo-
5b,17b-cholan-24-one (7e)
Yield 190 mg (64%). Oil. IR (neat) 3428, 2970, 1718, 1511 cm–1
;
1H NMR (300 MHz, CDCl3): d = 6.66 (d, J = 8.1 Hz, 2H), 6.28 (d,
J = 3.8 Hz, 2H), 4.56 (d, J = 6.4 Hz, 1H, H-12), 4.39 (m, 1H, H-3b),
3.74 (s, 3H, OCH3), 3.48 (m, 1H, H-7b), 3.16 (dd, J = 3.6, 4.1 Hz,
1H, H-11), 2.02 (s, 3H, CH3C@O), 2.01 (s, 3H, CH3C@O), 0.99 (d,
J = 6.4 Hz, 3H, H-21), 0.92 (s, 3H, H-19), 0.79 (s, 3H, H-18); 13C
NMR (75 MHz, CDCl3): d = 174.6, 170.8, 170.3, 149.2, 139.7, 117.4
(2C), 114.8 (2C), 90.6, 72.9, 71.6, 55.8, 49.9, 47.7, 47.4, 44.8, 38.2,
37.8, 35.6, 35.2, 34.7, 34.1, 33.9, 33.5, 31.7, 31.6, 30.6, 28.4, 27.9,
27.1, 21.6, 21.2, 18.7, 11.6. HRMS Calcd. for C35H49NO7 595.3509,
found 595.3514.
2.13. Methyl 3
cholan-24-one (7j)
a,7a-diacetyl-11b-naphthylamino-12a-oxo-5b,17b-
Yield 205 mg (66%). Oil. IR (neat) 3450, 2929, 1716, 1040 cm–1
;
1H NMR (300 MHz, CDCl3): d = 7.62 (m, 3H), 7.28 (m, 3H), 6.59 (m,
1H), 4.39 (d, J = 4.0 Hz, 1H, H-12), 4.32 (m, 1H, H-3b), 3.62 (m, 1H,
H-7b), 3.06 (dd, J = 3.7, 3.9 Hz, 1H, H-11), 2.04 (s, 3H, CH3C@O),
2.02 (s, 3H, CH3C@O), 1.12 (d, J = 6.3 Hz, 3H, H-21), 0.93 (s, 3H,
H-19), 0.72 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 173.8,
170.6, 170.1, 147.9, 134.8, 129.2, 128.7, 126.9, 126.6, 125.4,
121.9, 118.8, 110.7, 90.7, 76.5, 73.7, 50.4, 48.1, 47.7, 44.7, 42.9,
35.7, 34.1, 33.9, 33.8, 33.1, 32.8, 31.6, 31.0, 30.5, 27.9, 27.6, 27.3,
24.2, 21.5, 21.1, 18.8, 11.4. HRMS Calcd. for C38H49NO6 615.356,
found 615.3564.
2.9. Methyl 3
a,7a-diacetyl-11b-(4-fluorophenyl)amino-12a-oxo-
5b,17b-cholan-24-one (7f)
Yield 245 mg (83%). Oil. IR (neat) 3435, 2990, 1712, 1058 cm–1
;
1H NMR (300 MHz, CDCl3): d = 6.62 (m, 2H), 6.31 (m, 2H), 4.39 (d,
J = 3.9 Hz, 1H, H-12), 4.09 (m, 1H, H-3b), 3.46 (m, 1H, H-7b), 3.07
(dd, J = 3.5, 4.1 Hz, 1H, H-11), 2.02 (s, 3H, CH3C@O), 2.01 (s, 3H,
CH3C@O), 1.04 (d, J = 6.3 Hz, 3H, H-21), 0.99 (s, 3H, H-19), 0.77
(s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 174.2, 170.6, 170.1,
153.9 (JC,F = 243.2 Hz), 146.4, 119.2 (2C, JC,F = 21 Hz), 117.6 (2C,
JC,F = 6.9 Hz), 91.1, 75.3, 73.9, 50.6, 47.9, 47.5, 44.6, 37.6, 35.4,
34.9, 34.2, 33.9, 33.2, 31.0, 30.9, 30.3, 28.2, 27.3, 27.1, 23.8, 21.6,
21.1, 18.6, 11.4. HRMS Calcd. for C34H46FNO6 583.3309, found
583.3313.
2.14. Methyl 3
cholan-24-one (8a)
a,7a-diacetyl-11b-benzylsulfanyl-12a-oxo-5b,17b-
Yield 215 mg (72%). Oil. IR (neat) 3448, 1715, 1607, 1041 cm–1
;
1H NMR (300 MHz, CDCl3): d = 7.12 (m, 5H), 4.59 (m, 1H, H-3b),
4.23 (d, J = 4.1 Hz, 1H, H-12), 3.46 (m, 1H, H-7b), 3.18 (s, 2H,
SCH2Ph), 3.02 (dd, J = 3.6, 3.9 Hz, 1H, H-11), 2.04 (s, 3H, CH3C@O),
2.01 (s, 3H, CH3C@O), 1.16 (d, J = 5.6 Hz, 3H, H-21), 0.98 (s, 3H, H-
19), 0.76 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 174.3, 170.8,
170.3, 137.9, 128.8 (2C), 127.9 (2C), 126.9, 90.8, 76.8, 73.2, 51.5,
48.8, 44.3, 43.2, 43.6, 41.9, 40.2, 37.9, 35.4, 35.0, 34.7, 34.2, 33.9,
33.3, 32.4, 31.6, 31.0, 30.7, 22.9, 21.7, 21.2, 18.1, 11.1. HRMS Calcd.
for C35H48O6S 596.3172, found 596.3176.
2.10. Methyl 3a,7a-diacetyl-11b-(4-trifluoromethyl)phenylamino-
12a-oxo-5b,17b-cholan-24-one (7g)
Yield 230 mg (72%). Oil. IR (neat) 3425, 1712, 1180, 880 cm–1
;
1H NMR (300 MHz, CDCl3): d = 7.19 (d, J = 7.9 Hz, 2H), 6.42 (d,
J = 8.1 Hz, 2H), 4.52 (d, J = 3.9 Hz, 1H, H-12), 4.17 (m, 1H, H-3b),
3.48 (m, 1H, H-7b), 3.13 (dd, J = 3.7, 4.0 Hz, 1H, H-11), 2.02 (s,
3H, CH3C@O), 2.01 (s, 3H, CH3C@O), 1.12 (d, J = 6.4 Hz, 3H, H-21),
0.87 (s, 3H, H-19), 0.79 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3):
d = 174.3, 170.6, 170.1, 151.6, 126.7 (2C, JC,F = 36.8 Hz), 124.6,
119.1 (JC,F = 264.3 Hz), 114.2 (2C, JC,F = 4.2 Hz), 92.0, 74.9, 73.6,
50.6, 47.9, 47.6, 44.2, 43.6, 38.9, 35.7, 35.2, 34.2, 33.9, 32.8, 31.7,
31.0, 30.1, 28.7, 27.6, 27.2, 24.3, 21.3, 21.0, 18.1, 11.3. HRMS Calcd.
for C35H46F3NO6 633.3277, found 633.3283.
2.15. Methyl 3
oxo-5b,17b-cholan-24-one (8b)
a,7a-diacetyl-11b-(p-methoxybenzyl)sulfanyl-12a-
Yield 195 mg (62%). Oil. IR (neat) 3418, 1726, 1492, 1265 cm–1
;
1H NMR (300 MHz, CDCl3): d = 7.02 (d, J = 8.6 Hz, 2H), 6.72 (d,
J = 8.1 Hz, 2H), 4.47 (m, 1H, H-3b), 4.19 (d, J = 3.9 Hz, 1H, H-12),
3.78 (s, 3H, OCH3), 3.42 (m, 1H, H-7b), 3.29 (s, 2H, SCH2Ph), 3.09
(dd, J = 3.6, 4.0 Hz, 1H, H-11), 2.01 (s, 3H, CH3C@O), 2.00 (s, 3H,
CH3C@O), 1.04 (s, 3H, H-19), 1.01 (d, J = 6.1 Hz, 3H, H-21), 0.79
(s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 174.6, 170.3, 170.5,
158.8, 129.8 (2C), 128.47, 115.1 (2C), 91.8, 75.8, 73.1, 55.2, 51.9,
48.4, 44.5, 43.2, 42.7, 42.0, 40.3, 38.6, 35.6, 35.1, 34.2, 34.0, 33.7,
33.2, 32.5, 31.3, 31.1, 28.8, 23.6, 21.2, 20.9, 17.8, 11.6. HRMS Calcd.
for C36H50O7S 626.3277, found 626.3281.
2.11. Methyl 3a,7a-diacetyl-11b-propylamino-12a-oxo-5b,17b-
cholan-24-one (7h)
Yield 185 mg (70%). Oil. IR (neat) 3431, 1721, 1264, 729 cm–1
;
1H NMR (300 MHz, CDCl3): d = 4.39 (d, J = 3.8 Hz, 1H, H-12), 4.12
(m, 1H, H-3b), 3.39 (m, 1H, H-7b), 3.11 (dd, J = 3.9, 4.1 Hz, 1H,
H-11), 2.63 (m, 2H, CH2NH), 2.03 (s, 3H, CH3C@O), 2.01 (s, 3H,
CH3C@O), 1.19 (d, J = 6.4 Hz, 3H, H-21), 1.02 (t, J = 6.5 Hz, 3H,
CH3), 0.98 (s, 3H, H-19), 0.76 (s, 3H, H-18); 13C NMR (75 MHz,
CDCl3): d = 173.7, 170.6, 170.5, 89.8, 72.9, 71.8, 51.6, 50.3, 47.8,
45.7, 44.9, 43.1, 38.9, 35.2, 34.9, 34.4, 33.8, 33.6, 31.5, 31.0, 30.8,
28.6, 27.9, 27.1, 24.3, 23.7, 21.6, 21.2, 18.6, 16.2, 11.7. HRMS Calcd.
for C31H49NO6 531.356, found 531.3564.
2.16. Methyl 3
cholan-24-one (8c)
a,7a-diacetyl-11b-phenylsulfanyl-12a-oxo-5b,17b-
Yield 250 mg (82%). Oil. IR (neat) 3420, 1716, 905, 744 cm–1; 1H
NMR (300 MHz, CDCl3): d = 7.32 (m, 5H), 4.53 (d, J = 4.1 Hz, 1H, H-
12), 4.39 (m, 1H, H-3b), 3.69 (m, 1H, H-7b), 3.04 (dd, J = 3.5, 3.8 Hz,
1H, H-11), 2.05 (s, 3H, CH3C@O), 2.03 (s, 3H, CH3C@O), 1.09 (d,
J = 6.2 Hz, 3H, H-21), 0.94 (s, 3H, H-19), 0.72 (s, 3H, H-18); 13C

M. Ibrahim-Ouali et al. / Steroids 77 (2012) 1092–1100
1095
NMR (75 MHz, CDCl3): d = 175.1, 170.7, 170.4, 136.5, 129.5 (2C),
126.2 (2C), 124.9, 90.9, 76.1, 73.9, 49.9, 47.8, 44.7, 44.5, 43.3,
38.7, 36.0, 34.8, 34.3, 33.9, 33.7, 31.2, 31.0, 30.4, 29.4, 27.6, 26.4,
23.5, 21.6, 21.3, 17.9, 10.9. HRMS Calcd. for C34H46O6S 582.3015,
found 582.3020.
2.21. Methyl 3
5b,17b-cholan-24-one (8h)
a,7a-diacetyl-11b-(2-methyl)-butylsulfanyl-12a-oxo-
Yield 180 mg (62%). Oil. IR (neat) 3422, 2984, 1712, 1370 cm–1
;
1H NMR (300 MHz, CDCl3): d = 4.33 (d, J = 4.1 Hz, 1H, H-12), 3.91
(m, 1H, H-3b), 3.42 (m, 1H, H-7b), 3.08 (dd, J = 3.8, 4.0 Hz, 1H, H-
11), 2.62 (m, 2H, CH2S), 2.03 (s, 3H, CH3C@O), 2.00 (s, 3H, CH3C@O),
1.16 (d, J = 6.0 Hz, 3H, CH3CH), 1.09 (d, J = 6.4 Hz, 3H, H-21), 1.01 (t,
J = 6.2 Hz, 3H, CH3CH2), 0.86 (s, 3H, H-19), 0.72 (s, 3H, H-18); 13C
NMR (75 MHz, CDCl3): d = 173.9, 170.6, 170.2, 90.7 (90.6), 75.3
(75.1), 73.7 (73.2), 51.6, 50.4 (50.2), 47.7 (47.4), 45.6, 44.4 (44.0),
43.7 (43.5), 37.7 (37.3), 36.2 (36.0), 34.7, 34.1 (34.0), 33.8 (33.5),
32.7 (32.4), 31.7 (31.3), 31.2, 29.9 (29.6), 28.2 (28.0), 27.7, 27.1
(27.4), 24.9, 23.2, 21.4 (21.1), 21.2 (20.6), 20.3 (20.0), 18.1 (17.9),
2.17. Methyl 3
a,7a-diacetyl-11b-(4-methylphenyl)sulfanyl-12a-oxo-
5b,17b-cholan-24-one (8d)
Yield 190 mg (64%). Oil. IR (neat) 3353, 2976, 1712, 1606 cm–1
;
1H NMR (300 MHz, CDCl3): d = 7.12 (d, J = 7.9 Hz, 2H), 6.83 (d,
J = 8.2 Hz, 2H), 4.59 (d, J = 4.0 Hz, 1H, H-12), 4.49 (m, 1H, H-3b),
3.57 (m, 1H, H-7b), 3.09 (dd, J = 3.9, 4.1 Hz, 1H, H-11), 2.41 (s,
3H, CH3Ph), 2.03 (s, 3H, CH3C@O), 2.00 (s, 3H, CH3C@O), 1.11 (d,
J = 6.1 Hz, 3H, H-21), 0.97 (s, 3H, H-19), 0.86 (s, 3H, H-18); 13C
NMR (75 MHz, CDCl3): d = 173.9, 170.9, 170.1, 136.8, 134.0, 128.6
(2C), 125.9 (2C), 90.5, 74.6, 73.2, 49.7, 47.7, 44.3, 43.7, 40.3, 37.2,
35.6, 35.3, 34.7, 34.2, 33.7, 31.9, 31.0, 29.7, 28.4, 27.6, 27.2, 24.6,
23.9, 21.4, 20.9, 17.7, 11.6. HRMS Calcd. for C35H48O6S 596.3172
found 596.3177.
15.6 (15.1), 11.4 (11.0), 10.9. HRMS Calcd. for
576.3485, found 576.3489.
C33H52O6S
2.22. Methyl 3a,7a-diacetyl-11b-(3-methyl)-butylsulfanyl-12a-oxo-
5b,17b-cholan-24-one (8i)
Yield 205 mg (72%). Oil. IR (neat) 3353, 1718, 1374, 1038 cm–1
;
1H NMR (300 MHz, CDCl3): d = 4.27 (d, J = 4.0 Hz, 1H, H-12), 3.86
(m, 1H, H-3b), 3.31 (m, 1H, H-7b), 3.02 (dd, J = 3.6, 3.9 Hz, 1H,
H-11), 2.64 (m, 2H, CH2S), 2.04 (s, 3H, CH3C@O), 2.01 (s, 3H,
CH3C@O), 1.13 (d, J = 6.3 Hz, 6H, (CH3)2CH), 1.06 (d, J = 6.4 Hz,
3H, H-21), 0.85 (s, 3H, H-19), 0.69 (s, 3H, H-18); 13C NMR
(75 MHz, CDCl3): d = 173.6, 170.7, 170.3, 89.9, 76.1, 73.8, 49.9,
49.7, 47.2, 45.6, 44.3, 43.6, 38.2, 37.3, 35.1, 34.6, 34.0, 33.3, 32.7,
31.6, 31.0, 30.4, 28.9, 27.6, 27.3, 24.4, 23.7, 22.5, 21.6, 21.0, 20.7,
18.6, 11.1. HRMS Calcd. for C33H52O6S 576.3485, found 576.3491.
2.18. Methyl 3
oxo-5b,17b-cholan-24-one (8e)
a,7a-diacetyl-11b-(4-methoxyphenyl)sulfanyl-12a-
Yield 200 mg (65%). Oil. IR (neat) 3455, 2965, 1718, 1609,
1502 cm–1 1H NMR (300 MHz, CDCl3): d = 6.98 (d, J = 8.3 Hz, 2H),
;
6.59 (d, J = 8.1 Hz, 2H), 4.52 (d, J = 4.1 Hz, 1H, H-12), 4.31 (m, 1H,
H-3b), 3.76 (s, 3H, OCH3), 3.50 (m, 1H, H-7b), 3.17 (dd, J = 3.8,
4.1 Hz, 1H, H-11), 2.02 (s, 3H, CH3C@O), 2.00 (s, 3H, CH3C@O),
1.02 (d, J = 6.4 Hz, 3H, H-21), 0.89 (s, 3H, H-19), 0.78 (s, 3H, H-
18); 13C NMR (75 MHz, CDCl3): d = 174.2, 170.4, 170.2, 157.9,
128.7, 127.8 (2C), 115.6 (2C), 90.1, 76.1, 73.4, 56.3, 50.6, 47.3,
41.7, 40.4, 37.8, 36.5, 35.4, 34.9, 34.7, 34.2, 33.5, 32.9, 31.8, 31.2,
29.6, 28.7, 27.5, 27.1, 21.5, 20.9, 17.6, 11.3. HRMS Calcd. for
2.23. Methyl 3a,7a-diacetyl-11b-(1-naphthyl)sulfanyl-12a-oxo-
5b,17b-cholan-24-one (8j)
Yield 200 mg (63%). Oil. IR (neat) 3387, 2951, 1734, 1471,
1035 cm–1 1H NMR (300 MHz, CDCl3): d = 7.74 (m, 1H), 7.65 (m,
C35H48O7S 612.3121, found 612.3126.
;
2H), 7.36 (m, 3H), 6.66 (m, 1H), 4.49 (d, J = 4.1 Hz, 1H, H-12),
4.33 (m, 1H, H-3b), 3.67 (m, 1H, H-7b), 3.11 (dd, J = 3.6, 3.9 Hz,
1H, H-11), 2.03 (s, 3H, CH3C@O), 2.02 (s, 3H, CH3C@O), 1.03 (d,
J = 6.4 Hz, 3H, H-21), 0.89 (s, 3H, H-19), 0.73 (s, 3H, H-18); 13C
NMR (75 MHz, CDCl3): d = 174.2, 170.9, 170.5, 135.9, 133.9,
128.9, 128.8, 128.6, 126.5, 126.4, 126.2, 124.8, 124.7, 89.4, 76.0,
73.1, 49.7, 49.5, 47.8, 44.9, 42.5, 35.3, 34.7, 33.6, 33.1, 33.0, 32.7,
31.2, 31.0, 30.6, 27.8, 27.4, 27.1, 24.0, 21.7, 21.2, 18.3, 11.3. HRMS
Calcd. for C38H48O6S 632.3172, found 632.3178.
2.19. Methyl 3
5b,17b-cholan-24-one (8f)
a,7a-diacetyl-11b-(4-fluorophenyl)sulfanyl-12a-oxo-
Yield 235 mg (78%). Oil. IR (neat) 3429, 2950, 1718, 1606,
1089 cm–1 1H NMR (300 MHz, CDCl3): d = 7.09 (m, 2H), 6.83 (m,
;
2H), 4.33 (d, J = 4.0 Hz, 1H, H-12), 4.05 (m, 1H, H-3b), 3.48 (m,
1H, H-7b), 3.02 (dd, J = 8.6, 3.9 Hz, 1H, H-11), 2.03 (s, 3H, CH3C@O),
2.01 (s, 3H, CH3C@O), 1.06 (d, J = 3.4 Hz, 3H, H-21), 0.83 (s, 3H,
H-19), 0.72 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 174.9,
170.7, 170.4, 158.3 (JC,F = 240.0 Hz), 133.8, 127.9 (2C, JC,F = 6.8 Hz),
115.2 (2C, JC,F = 21.0 Hz), 89.9, 76.6, 73.7, 51.3, 49.7, 45.6, 42.8,
40.9, 37.2, 37.8, 35.3, 35.1, 34.6, 34.0, 33.7, 33.4, 31.5, 30.9, 28.6,
28.4, 27.9, 27.2, 21.9, 21.0, 17.7, 11.2. HRMS Calcd. for C34H45FO6S
600.2921, found 600.2925.
2.24. General procedure for the preparation of sulfones 10
0.79 mmol of compound 8 were dissolved in CH2Cl2 (15 mL),
under argon. The solution was cooled at 0 °C and m-CPBA (0.39 g,
1.58 mmol) was added. After stirring at room temperature for
24 h, the mixture was hydrolyzed with a saturated solution of
NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2
(3 Â 25 mL). The organic phase was dried with MgSO4, filtered
and concentrated in vacuo. The residue was purified by flash chro-
matography on silica gel to afford the corresponding sulfone 10.
2.20. Methyl 3
cholan-24-one (8g)
a,7a-diacetyl-11b-propylsulfanyl-12a-oxo-5b,17b-
Yield 180 mg (66%). Oil. IR (neat) 3420, 2981, 1721, 1370,
1048 cm–1 1H NMR (300 MHz, CDCl3): d = 4.27 (d, J = 3.9 Hz, 1H,
;
2.25. Methyl 3a,7a-diacetyl-11b-benzylsulfonyl-12a-oxo-5b,17b-
H-12), 3.96 (m, 1H, H-3b), 3.31 (m, 1H, H-7b), 3.04 (dd, J = 3.7,
3.9 Hz, 1H, H-11), 2.57 (m, 2H, CH2S), 2.04 (s, 3H, CH3C@O), 2.02
(s, 3H, CH3C@O), 1.12 (d, J = 6.4 Hz, 3H, H-21), 0.99 (t, J = 6.5 Hz,
3H, CH3), 0.89 (s, 3H, H-19), 0.74 (s, 3H, H-18); 13C NMR
(75 MHz, CDCl3): d = 174.2, 170.8, 170.1, 89.9, 74.9, 72.1, 52.1,
50.6, 48.2, 44.9, 43.7, 42.1, 38.7, 36.4, 34.3, 34.0, 33.7, 33.2, 31.2,
31.0, 30.7, 28.4, 27.6, 26.9, 25.3, 23.4, 21.6, 21.3, 18.3, 15.2, 11.2.
HRMS Calcd. for C31H48O6S 548.3172, found 548.3179.
cholan-24-one (10a)
Yield 375 mg (76%). Oil. IR (neat) 3387, 2951, 1719, 1359,
1150 cm–1 1H NMR (300 MHz, CDCl3): d = 7.16 (m, 5H), 4.82 (s,
;
2H, SO2CH2Ph), 4.54 (m, 1H, H-3b), 3.96 (d, J = 4.0 Hz, 1H, H-12),
3.57 (dd, J = 3.6, 3.9 Hz, 1H, H-11), 3.41 (m, 1H, H-7b), 2.03 (s,
3H, CH3C@O), 2.02 (s, 3H, CH3C@O), 1.12 (d, J = 5.6 Hz, 3H, H-21),
0.89 (s, 3H, H-19), 0.77 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3):

1096
M. Ibrahim-Ouali et al. / Steroids 77 (2012) 1092–1100
d = 174.0, 170.8, 170.2, 136.3, 129.2 (2C), 127.9 (2C), 124.1, 81.4,
76.8, 74.2, 57.1, 50.6, 48.8, 44.9, 43.5, 43.1, 41.9, 40.6, 39.4, 35.7,
35.1, 34.6, 34.2, 33.8, 33.1, 31.9, 31.6, 31.0, 27.3, 21.6, 21.3, 18.7,
11.4. HRMS Calcd. for C35H48O8 S 628.307, found 628.3075.
2.30. Methyl 3
5b,17b-cholan-24-one (10f)
a,7a-diacetyl-11b-(4-fluorobenzene)sulfonyl-12a-oxo-
Yield 375 mg (75%). Oil. IR (neat) 3429, 1726, 1330, 1042 cm–1
;
1H NMR (300 MHz, CDCl3): d = 8.01 (m, 2H), 7.32 (m, 2H), 4.03 (m,
1H, H-3b), 3.89 (d, J = 4.0 Hz, 1H, H-12), 3.71 (dd, J = 3.6, 3.9 Hz, 1H,
H-11), 3.46 (m, 1H, H-7b), 2.03 (s, 3H, CH3C@O), 2.01 (s, 3H,
CH3C@O), 1.01 (d, J = 6.3 Hz, 3H, H-21), 0.79 (s, 3H, H-19), 0.66
(s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 175.1, 170.6, 170.2,
163.2 (JC,F = 261.8 Hz), 134.5, 129.9 (2C, JC,F = 6.4 Hz), 116.3 (2C,
JC,F = 16.1 Hz), 83.9, 75.8, 73.3, 50.9, 50.0, 45.1, 41.7, 40.1, 36.8,
36.7, 35.3, 34.3, 34.2, 33.8, 33.4, 32.9, 32.6, 30.5, 28.4, 27.6, 27.2,
21.6, 21.3, 17.4, 10.9. HRMS Calcd. for C34H45FO8S 632.2819, found
632.2824.
2.26. Methyl 3a,7a-diacetyl-11b-(p-methoxybenzyl)sulfonyl-12a-
oxo-5b,17b-cholan-24-one (10b)
Yield 385 mg (74%). Oil. IR (neat) 3418, 2961, 1720, 1340,
1145 cm–1 1H NMR (300 MHz, CDCl3): d = 7.09 (d, J = 8.1 Hz, 2H),
;
6.78 (d, J = 7.9 Hz, 2H), 4.41 (m, 1H, H-3b), 4.69 (s, 2H, SO2CH2Ph),
3.88 (d, J = 4.1 Hz, 1H, H-12), 3.76 (s, 3H, OCH3), 3.64 (dd, J = 3.5,
4.0 Hz, 1H, H-11), 3.46 (m, 1H, H-7b), 2.01 (s, 3H, CH3C@O), 2.00
(s, 3H, CH3C@O), 1.12 (s, 3H, H-19), 1.02 (d, J = 6.1 Hz, 3H, H-21),
0.77 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 174.8, 170.6,
170.1, 159.7, 130.6 (2C), 116.9, 114.7 (2C), 82.3, 76.9, 73.7, 56.9,
56.1, 50.7, 47.9, 44.7, 44.2, 42.3, 40.7, 37.3, 36.5, 35.3, 34.1, 33.9,
33.6, 32.9, 32.4, 31.7, 29.6, 28.4, 27.6, 21.8, 21.6, 17.9, 11.5. HRMS
Calcd. for C36H50O9S 658.3176, found 658.3180.
2.31. Methyl 3a,7a-diacetyl-11b-propylsulfonyl-12a-oxo-5b,17b-
cholan-24-one (10g)
Yield 180 mg (86%). Oil. IR (neat) 3422, 1724, 1335, 1048 cm–1
;
1H NMR (300 MHz, CDCl3): d = 3.96 (d, J = 4.1 Hz, 1H, H-12), 3.88
(m, 1H, H-3b), 3.64 (dd, J = 3.6, 3.9 Hz, 1H, H-11), 3.39 (m, 1H,
H-7b), 3.21 (m, 2H, CH2SO2), 2.03 (s, 3H, CH3C@O), 2.02 (s, 3H,
CH3C@O), 1.12 (d, J = 6.4 Hz, 3H, H-21), 0.96 (t, J = 6.5 Hz, 3H,
CH3), 0.88 (s, 3H, H-19), 0.72 (s, 3H, H-18); 13C NMR (75 MHz,
CDCl3): d = 174.6, 170.2, 169.9, 82.6, 75.1, 73.3, 53.4, 51.0, 48.6,
44.7, 42.6, 41.1, 36.3, 34.4, 34.2, 33.6, 33.4, 31.6, 31.0, 30.6, 28.4,
27.6, 26.9, 25.3, 23.4, 21.9, 21.3, 17.6, 15.9, 13.6, 11.4. HRMS Calcd.
for C31H48O8S 580.307, found 580.3075.
2.27. Methyl 3a,7a-diacetyl-11b-benzenesulfonyl-12a-oxo-5b,17b-
cholan-24-one (10c)
Yield 400 mg (82%). Oil. IR (neat) 3424, 1718, 1338, 1130 cm–1
;
1H NMR (300 MHz, CDCl3): d = 7.98 (m, 2H), 7.67 (m, 2H), 7.34 (m,
1H), 4.48 (m, 1H, H-3b), 3.92 (d, J = 4.0 Hz, 1H, H-12), 3.72 (dd,
J = 3.7, 3.9 Hz, 1H, H-11), 3.66 (m, 1H, H-7b), 2.04 (s, 3H, CH3C@O),
2.00 (s, 3H, CH3C@O), 1.06 (d, J = 6.4 Hz, 3H, H-21), 0.92 (s, 3H, H-
19), 0.74 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3): d = 174.5, 170.6,
169.9, 138.9, 134.2, 129.9 (2C), 127.4 (2C), 88.6, 76.4, 72.9, 50.7,
49.8, 44.8, 44.0, 42.6, 36.9, 35.7, 34.9, 34.1, 33.6, 32.9, 31.4, 31.1,
30.4, 28.4, 27.6, 24.4, 23.5, 21.6, 21.1, 17.6, 10.7. HRMS Calcd. for
2.32. Methyl 3a,7a-diacetyl-11b-(2-methyl)-butylsulfonyl-12a-oxo-
5b,17b-cholan-24-one (10h)
Yield 370 mg (77%). Oil. IR (neat) 3429, 1718, 1336, 1059 cm–1
;
1H NMR (300 MHz, CDCl3): d = 4.01 (d, J = 3.9 Hz, 1H, H-12), 3.87
(m, 1H, H-3b), 3.67 (dd, J = 3.6, 4.0 Hz, 1H, H-11), 3.41 (m, 1H, H-
7b), 3.32 (m, 2H, CH2SO2), 2.03 (s, 3H, CH3C@O), 2.01 (s, 3H,
CH3C@O), 1.19 (d, J = 6.3 Hz, 3H, CH3CH), 1.03 (d, J = 6.4 Hz, 3H,
H-21), 0.99 (t, J = 6.4 Hz, 3H, CH3CH2), 0.82 (s, 3H, H-19), 0.69 (s,
3H, H-18); 13C NMR (75 MHz, CDCl3): d = 175.1, 170.8, 170.3,
82.4, 74.9, 73.7, 54.7, 50.6, 48.6, 45.4, 41.2, 40.1, 37.3, 35.7, 34.9,
34.2, 33.6, 32.9, 31.0, 29.7, 29.4, 28.4, 27.6, 27.2, 26.1, 24.3, 21.6,
21.5, 19.7, 19.6, 17.9, 12.7, 11.6. HRMS Calcd. for C33H52O8S
608.3383, found 608.3387.
C34H46O8S 614.2913, found 614.2919.
2.28. Methyl 3a,7a-diacetyl-11b-(4-methylbenzene)sulfonyl-12a-
oxo-5b,17b-cholan-24-one (10d)
Yield 390 mg (78%). Oil. IR (neat) 3353, 1715, 1345, 1128 cm–1
;
1H NMR (300 MHz, CDCl3): d = 7.94 (d, J = 7.9 Hz, 2H), 7.39 (d,
J = 8.2 Hz, 2H), 4.37 (m, 1H, H-3b), 4.02 (d, J = 3.9 Hz, 1H, H-12),
3.85 (dd, J = 3.8, 4.1 Hz, 1H, H-11), 3.52 (m, 1H, H-7b), 2.39 (s,
3H, CH3Ph), 2.03 (s, 3H, CH3C@O), 2.02 (s, 3H, CH3C@O), 1.13 (d,
J = 6.3 Hz, 3H, H-21), 0.89 (s, 3H, H-19), 0.72 (s, 3H, H-18); 13C
NMR (75 MHz, CDCl3): d = 174.7, 170.8, 170.3, 141.9, 135.4, 129.6
(2C), 128.9 (2C), 83.2, 76.1, 73.9, 51.2, 50.6, 44.7, 41.2, 40.6, 36.0,
34.6, 34.0, 33.7, 33.2, 32.9, 31.0, 29.9, 29.6, 28.4, 27.6, 27.4, 24.6,
24.3, 21.7, 20.9, 17.4, 11.0. HRMS Calcd. for C35H48O8S 628.307
found 628.3074.
2.33. Methyl 3a,7a-diacetyl-11b-(3-methyl)-butylsulfonyl-12a-oxo-
5b,17b-cholan-24-one (10i)
Yield 395 mg (82%). Oil. IR (neat) 3426, 1721, 1340, 1046 cm–1
;
1H NMR (300 MHz, CDCl3): d = 3.95 (d, J = 4.1 Hz, 1H, H-12), 3.77
(m, 1H, H-3b), 3.62 (dd, J = 3.7, 3.9 Hz, 1H, H-11), 3.54 (m, 2H,
CH2SO2), 3.39 (m, 1H, H-7b), 2.04 (s, 3H, CH3C@O), 2.02 (s, 3H,
CH3C@O), 1.09 (d, J = 6.4 Hz, 6H, (CH3)2CH), 1.01 (d, J = 6.3 Hz,
3H, H-21), 0.84 (s, 3H, H-19), 0.66 (s, 3H, H-18); 13C NMR
(75 MHz, CDCl3): d = 173.9, 170.4, 170.1, 82.9, 75.8, 73.1, 50.8,
48.9, 48.0, 45.3, 44.7, 39.6, 37.3, 35.7, 34.2, 33.9, 33.2, 32.8, 32.4,
31.7, 31.3, 29.4, 28.7, 27.4, 27.1, 26.9, 23.6, 23.1, 21.8, 21.3, 20.6,
18.4, 11.1. HRMS Calcd. for C33H52O8S 608.3383, found 608.3386.
2.29. Methyl 3a,7a-diacetyl-11b-(4-methoxybenzene)sulfonyl-12a-
oxo-5b,17b-cholan-24-one (10e)
Yield 365 mg (72%). Oil. IR (neat) 3455, 2965, 1718, 1374,
1089 cm–1 1H NMR (300 MHz, CDCl3): d = 8.06 (d, J = 8.6 Hz, 2H),
;
7.12 (d, J = 8.2 Hz, 2H), 4.43 (m, 1H, H-3b), 3.96 (d, J = 3.9 Hz, 1H,
H-12), 3.81 (dd, J = 3.8, 4.0 Hz, 1H, H-11), 3.77 (s, 3H, OCH3), 3.59
(m, 1H, H-7b), 2.02 (s, 3H, CH3C@O), 2.00 (s, 3H, CH3C@O), 1.06
(d, J = 6.4 Hz, 3H, H-21), 0.82 (s, 3H, H-19), 0.69 (s, 3H, H-18); 13C
NMR (75 MHz, CDCl3): d = 174.9, 170.8, 170.1, 159.9, 131.7, 129.8
(2C), 115.1 (2C), 82.7, 76.5, 73.6, 56.4, 50.3, 49.9, 44.7, 39.4, 37.2,
36.1, 35.7, 34.4, 34.2, 33.8, 33.7, 32.6, 31.5, 31.0, 29.4, 28.3, 27.4,
26.9, 21.5, 21.1, 17.9, 11.1. HRMS Calcd. for C35H48O9S 644.3019,
found 644.3023.
2.34. Methyl 3
cholan-24-one (10j)
a,7a-diacetyl-11b-naphthylsulfonyl-12a-oxo-5b,17b-
Yield 355 mg (68%). Oil. IR (neat) 3436, 1715, 1356, 1048 cm–1
;
1H NMR (300 MHz, CDCl3): d = 8.36 (m, 1H), 8.04 (m, 2H), 7.87 (m,
3H), 7.41 (m, 1H), 4.09 (d, J = 4.1 Hz, 1H, H-12), 4.29 (m, 1H, H-3b),
3.73 (dd, J = 3.8, 4.0 Hz, 1H, H-11), 3.56 (m, 1H, H-7b), 2.03 (s, 3H,
CH3C@O), 2.02 (s, 3H, CH3C@O), 1.07 (d, J = 6.4 Hz, 3H, H-21), 0.83

M. Ibrahim-Ouali et al. / Steroids 77 (2012) 1092–1100
1097
O
O
HO
HO
OR
OMe
b
c
HO
OH
AcO
OAc
H
H
1 R = H
3
a
2 R = CH3
O
O
MsO
OMe
OMe
d
e
AcO
OAc
AcO
OAc
H
H
4
5
O
O
O
OMe
O
RHN
12
11
9
f
AcO
OAc
AcO
OAc
H
H
6
7
Reaction conditions : (a) MeOH, PTSA, Δ, 99%; (b) Ac2O, pyridine, DMAP, 87%; (c) MsCl, pyridine, 0° C to r.t., 24 h,
100%; (d) AcOK, HMPT, 100 °C, 48 h, 80%; (e) m-CPBA, CH2Cl2, r.t., 24 h, 92%; (f) RNH2, EtOH/toluene (1/1), Δ, 24 h.
Scheme 2. Stereoselective synthesis of 11-amino-cholano-24,12-lactones from cholic acid.
Table 1
Pentacyclic steroids 7a-j and 8a-j.
Entry
1
Amines RNH2
NH2
Yielda of 7
7a: 81%
Thiols RSH
Yielda of 8
8a: 72%
SH
2
7b: 65%
8b: 62%
NH2
SH
H3CO
H3CO
3
4
5
6
7
8
7c: 88%
7d: 67%
7e: 64%
7f: 83%
7g: 72%
7h: 70%
8c: 82%
8d: 64%
8e: 65%
8f: 78%
8g: 66%
8h: 62%
NH2
SH
CH3
CH3O
F
NH2
NH2
H3C
CH3O
F
SH
SH
NH2
NH2
SH
SH
SH
CF3
NH2
NH2
NH2
9
7i: 75%
7j: 66%
8i: 72%
8j: 63%
SH
10
SH
a
Yields are given for isolated products.
(s, 3H, H-19), 0.69 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3):
d = 174.4, 170.7, 170.3, 139.4, 138.7, 134.9, 129.6, 128.4, 127.8,
126.9, 126.7, 126.0, 124.9, 82.6, 75.1, 73.6, 51.2, 50.6, 49.8, 45.9,
39.4, 36.9, 35.6, 34.2, 33.9, 33.7, 32.8, 32.1, 31.7, 31.5, 28.9, 27.6,

1098
M. Ibrahim-Ouali et al. / Steroids 77 (2012) 1092–1100
O
O
O
O
O
O
O
O
S
OMe
R
O
O
RS
S
R
m-CPBA
a
AcO
OAc
AcO
OAc
AcO
OAc
AcO
OAc
CH2Cl2, r.t.
H
H
6
H
H
8
10
8
Reaction condition : (a) RSH, EtOH/toluene (1/1Δ),, 24 h.
Scheme 5. Synthesis of sulfones 10.
Scheme 3. Stereoselective synthesis of 11-thio-cholano-24,12-lactones from cholic
acid.
Table 2
Sulfones 10a-j.
27.2, 22.1, 21.9, 21.4, 17.6, 10.9. HRMS Calcd. for C38H48O8S
664.307, found 664.3076.
Entry 8
Product 10: yield
8a
8b
8c
8d
8e
8f
8g
8h
8i
76%
74%
82%
78%
72%
75%
86%
77%
82%
68%
2.35. Methyl 3
cholan-24-one (11)
a,7a-diacetyl-11b-cyanylseleno-12a-oxo-5b,17b-
Epoxide 6 (0.5 g, 1 mmol) and potassium selenocyanate (0.15 g,
1 mmol) in acetone (30 mL) were heated under reflux for 24 h.
After evaporation of the solvent, the product was dissolved in
diethyl ether (20 mL). The solution was washed with saturated
brine (10 mL) and with water (10 mL) and dried over anhydrous
magnesium sulfate. Evaporation of the solvent left a residue, which
was chromatographed on silica gel, eluted with petroleum ether/
diethyl ether: 7/3. Compound 11 was isolated in 66% yield
(0.38 g) as an oil.
8j
amines. During this step, an intramolecular lactonization was also
observed leading to the corresponding 11-amino-cholano-24,12-
lactones 7. This reaction, stereo- and regioselective, was very effi-
cient. The yields of the relative lactones were depicted in Table 1.
As a continuation of our synthetic and stereochemical studies
on steroidal systems containing an heteroatom, a similar strategy
was used to obtain pentacyclic steroids 8 possessing a thiol func-
IR (neat) 3349, 2931, 2128, 1352, 1045 cm–1; 1H NMR (300 MHz,
CDCl3): d = 4.37 (m, 1H, H-3b), 3.98 (d, J = 4.0 Hz, 1H, H-12), 2.52
(dd, J = 3.6, 3.9 Hz, 1H, H-11), 3.51 (m, 1H, H-7b), 2.03 (s, 3H,
CH3C@O), 2.02 (s, 3H, CH3C@O), 1.09 (d, J = 5.6 Hz, 3H, H-21), 0.88
(s, 3H, H-19), 0.72 (s, 3H, H-18); 13C NMR (75 MHz, CDCl3):
d = 175.1, 170.5, 170.1, 101.8, 78.7, 75.3, 70.8, 50.3, 48.6, 44.2,
39.4, 37.8, 36.4, 35.3, 34.9, 33.8, 33.2, 32.6, 31.2, 30.6, 29.3, 28.4,
27.6, 27.1, 24.6, 21.9, 21.6, 18.3, 10.9. HRMS Calcd. for C29H41NO6Se
579.2099, found 579.2103.
tion at the C-11 position (Scheme 3). Thus, 11a,12a-epoxide 6
was treated with different nucleophilic thiols in EtOH/toluene (1/
1) at reflux during 24 h, affording steroidal lactones 8. The yields
of these new lactones are depicted in Table 1. Here too, the reaction
was very efficient, stereo- and regioselective, and this selectivity
can be rationalized as shown in Scheme 4. The structure of these
new pentacyclic steroids 8 was completely characterized by NMR
(400 MHz) and mass spectroscopic methods (see experimental
part). The NMR spectra showed a disappearance of the characteris-
tic singlet of the lateral chain at dH 3.6 ppm (s, C-24-OMe) and the
3. Results and discussion
We recently described a new synthesis of pentacyclic steroids
by stereoselective epoxide ring opening [18] (Scheme 2). Our strat-
egy is based on a diastereoselective epoxidation and a stereoselec-
tive epoxide ring opening employing nucleophilic species. The
methyl 3,7-diacetylchol-11-enate 5 was prepared from cholic acid,
a commercial bile acid inexpensive and readily available, according
to the previously described procedure [15] in 4 steps and a 70%
overall yield. Epoxidation of 5 with m-CPBA in CH2Cl2 afforded
signal of H-(11) (J ꢀ 4 Hz) confirm its
a position.
As depicted in Scheme 4, the nucleophilic attack in the
a-epoxide
ring opening, made exclusively on the least sterically hindered car-
bon epoxide (C11) (SN2 mechanism), produces a trans-hydroxy
amine or sulfide 9, which is not isolated.
It is worth pointing out, by analyzing Table 1, that the epoxide ring
opening is not sensitive to electronic effects of the aromatic moiety in
the 11a,12a-epoxide 6 in high selectivity and good yield. Then, a
selective epoxide ring opening was applied with nucleophilic
intramolecular
lactonization
not sterically favorable
O
O
anti-epoxide ring-
HO
opening suitable to
a SN2 mechanism
OMe
OMe
O
R'
11
7
or
AcO
OAc
AcO
OAc
8
H
H
9
6
syn-epoxide ring-
opening not favorable
R' = NHR or SR
Scheme 4. Proposed mechanism of epoxide ring opening.

M. Ibrahim-Ouali et al. / Steroids 77 (2012) 1092–1100
1099
O
O
OMe
O
NCSe
a
AcO
OAc
AcO
OAc
H
H
6
11
Reaction condition : (a) KSeCN, acetone, Δ, 24 h, 66%.
Scheme 6. Stereoselective synthesis of a steroidal 11-selenocyanate 11.
[4] Pinder AR. Steroidal alkaloids in Rodd’s chemistry of carbon
compounds. Amsterdam: Elsevier; 1998.
[5] Ibrahim-Ouali M. Synthesis of pentacyclic steroids. Steroids 2008;73:775–97.
the amines or thiols. Good yields were obtained with nucleophiles
possessing both activating and deactivating R groups. The reaction
is also not sensitive to steric effects as shown by the entry 10: the
bulky naphthyl group was introduced in good yield (Table 1).
We turned then our attention to the preparation of steroidal
sulfone derivatives. The synthetic utility of organic sulfur com-
pounds has been reviewed [19–22]. Otherwise, compounds con-
taining a sulfide, sulfoxide or sulfone moiety present not only a
synthetic interest but also for some of them a medicinal relevance
[23,24]. Indeed, during metabolism organic sulfides can undergo
oxidation to sulfoxides and then to sulfones [25]. Thus, for exam-
ple, tazofelone an inflammatory bowel disease agent, undergoes
oxidative metabolism forming stereoisomeric sulfoxides [26].
So, we envisaged to oxidize our 11-thio-cholano-24,12-lactones
by using a chemical method [27,28]. The reaction was conducted
with 2 equiv of m-CPBA in dichloromethane at room temperature
(Scheme 5). The corresponding steroids 10a-j possessing a sulfone
moiety at C-11, were isolated in good yields as reported in Table 2.
Having transformed efficiently our 11-thio derivatives into sulf-
ones, we turned then our attention to the introduction of a selena
moiety at the C-11 position of the steroidal skeleton. Organosele-
nium compounds have been documented as promising pharmaco-
logical agents against a number of diseases. Indeed, compounds
containing selenium can possess biological properties and have
been used as antiviral, antihypertensive, antibacterial or chemo-
preventive anticancer agents [29,30]. There are several reports in
the literature describing the antitumoral activity of selenium com-
pounds via apoptosis in cancer cells induced by the generation of
ROS in a pro-oxidant fashion [31–35].
Thus, epoxide 6 was dissolved in acetone containing potassium
selenocyanate [36] and was heated under reflux for 24 h, to give
the steroidal selenocyanate 11 in good yield (see Scheme 6).
In conclusion, this paper describes a versatile and stereoselec-
tive synthesis of pentacyclic steroids from commercially available
cholic acid. Moreover, all these steroids possess a functional group
at the C-11 position of the steroidal skeleton, which is a key posi-
tion from a biological point of view. The key steps of this synthesis
are an asymmetric epoxidation and a stereoselective epoxide ring
opening. Tests to check the biological activity of these steroids
and application of this strategy to obtain new structures are being
conducted by our group.
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Acknowledgements
We are indebted to Dr R. Faure for his assistance in NMR mea-
surements and to P. Filippini for helpful comments.
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